. doi: 10.1016/j.virs.2024.01.008
Citation: Xiangpeng Sheng, Yi Yang, Min Zhu, Linlin Zhou, Fang Zhu, Yuanfei Zhu, Siying Dong, Hui Kong, Honghua Wang, Ji Jiang, Mingyue Wan, Mingyang Feng, Qiang Deng, Yumin Xu, Qing You, Ronggui Hu. Non-proteolytic ubiquitination of HBx controls HBV replication .VIROLOGICA SINICA, 2024, 39(2) : 338-342.  http://dx.doi.org/10.1016/j.virs.2024.01.008

乙肝病毒X蛋白的非降解性泛素化修饰限制了乙肝病毒的复制

  • 乙型肝炎病毒(HBV)感染是肝细胞癌形成的主要原因,目前仍然严重危害人类健康。乙型肝炎病毒表达一种多功能的X蛋白(HBx),该蛋白不仅仅影响宿主细胞的许多生命活动,还能通过招募DDB1相关的E3泛素连接酶来降解宿主Smc5/6,从而促进HBV感染。尽管大量的研究拓宽了我们对HBx功能的了解,但针对HBx的调控机制还没有充分阐释。在这项研究中,我们发现宿主的E3泛素连接酶TRIM21可以通过对HBx进行非降解性的泛素修饰来抑制HBV的感染和复制。我们发现TRIM21在细胞内的表达水平与HBV的复制呈现负相关的关系。并且,TRIM21可以直接结合HBx蛋白并催化了HBx上非赖氨酸位点的泛素修饰,此种泛素化修饰并不影响HBx的稳定性。更为重要的是,突变了泛素化位点的HBx可以更强地招募DDB1,并促进HBV的复制。这些研究结果为我们更好地理解HBx的调节机制提供了基础,并为针对HBV感染的药物开发提供新思路。

Non-proteolytic ubiquitination of HBx controls HBV replication

  • Highlights
    1. The expression level of TRIM21 in patients is negatively correlated with the replication and integration of HBV.
    2. TRIM21 was found to trigger non-proteolytic ubiquitination of X protein of HBV.
    3. This study proposes that the PRYSPRY and RING domains in TRIM21 dimer can form a docking conformation for HBx binding.
    4. TRIM21-mediated HBx ubiquitination disrupts the DDB1 recruitment to HBx and stabilize Smc6.

  • 加载中
    1. Decorsière A, Mueller H, Van Breugel PC, Abdul F, Gerossier L, Beran RK, Livingston CM, Niu C, Fletcher SP, Hantz O. 2016. Hepatitis b virus x protein identifies the smc5/6 complex as a host restriction factor. Nature, 531:386-389.

    2. Dong H, Zhang L, Qian Z, Zhu X, Zhu G, Chen Y, Xie X, Ye Q, Zang J, Ren Z. 2015. Identification of hbv-mll4 integration and its molecular basis in chinese hepatocellular carcinoma. PloS one, 10:e0123175.

    3. Foss S, Watkinson R, Sandlie I, James LC, Andersen JT. 2015. Trim21:A cytosolic fc receptor with broad antibody isotype specificity. Immunol. Rev., 268:328-339.

    4. Keeble AH, Khan Z, Forster A, James LC. 2008. Trim21 is an igg receptor that is structurally, thermodynamically, and kinetically conserved. Proc Natl Acad Sci U S A, 105:6045-6050.

    5. Lamontagne RJ, Bagga S, Bouchard MJ. 2016. Hepatitis b virus molecular biology and pathogenesis. Hepatoma Res, 2:163-186.

    6. Li C, Han T, Guo R, Chen P, Peng C, Prag G, Hu R. 2020. An integrative synthetic biology approach to interrogating cellular ubiquitin and ufm signaling. Int. J. Mol. Sci., 21:4231.

    7. Mu T, Zhao X, Zhu Y, Fan H, Tang H. 2020. The e3 ubiquitin ligase trim21 promotes hbv DNA polymerase degradation. Viruses, 12:346.

    8. Nejepinska J, Malik R, Moravec M, Svoboda P. 2012. Deep sequencing reveals complex spurious transcription from transiently transfected plasmids. PloS one, 7:e43283.

    9. Nejepinska J, Malik R, Wagner S, Svoboda P. 2014. Reporters transiently transfected into mammalian cells are highly sensitive to translational repression induced by dsrna expression. PloS one, 9:e87517.

    10. Qi Z, Li G, Hu H, Yang C, Zhang X, Leng Q, Xie Y, Yu D, Zhang X, Gao Y. 2014. Recombinant covalently closed circular hepatitis b virus DNA induces prolonged viral persistence in immunocompetent mice. Virol. J., 88:8045-8056.

    11. Sheng X, Xia Z, Yang H, Hu R. 2023. The ubiquitin codes in cellular stress responses. Protein & Cell:pwad045.

    12. Sheng X, You Q, Zhu H, Li Q, Gao H, Wang H, You C, Meng Q, Nie Y, Zhang X. 2020. Enterohemorrhagic e. Coli effector nlel disrupts host nf-κb signaling by targeting multiple host proteins. J. Mol. Cell Biol, 12:318-321.

    13. Song Y, Li M, Wang Y, Zhang H, Wei L, Xu W. 2021. E3 ubiquitin ligase trim21 restricts hepatitis b virus replication by targeting hbx for proteasomal degradation. Antivir. Res., 192:105107.

    14. Stepanenko AA, Heng HH. 2017. Transient and stable vector transfection:Pitfalls, off-target effects, artifacts. Mutat. Res.-Rev. Mutat. Res, 773:91-103.

    15. van Breugel PC, Robert EI, Mueller H, Decorsière A, Zoulim F, Hantz O, Strubin M. 2012. Hepatitis b virus x protein stimulates gene expression selectively from extrachromosomal DNA templates. Hepatology, 56:2116-2124.

    16. Yang L, Zou T, Chen Y, Zhao Y, Wu X, Li M, Du F, Chen Y, Xiao Z, Shen J. 2022. Hepatitis b virus x protein mediated epigenetic alterations in the pathogenesis of hepatocellular carcinoma. Hepatol. Int.:1-14.

    17. Zhang J-F, Xiong H-L, Cao J-L, Wang S-J, Guo X-R, Lin B-Y, Zhang Y, Zhao J-H, Wang Y-B, Zhang T-Y. 2018. A cell-penetrating whole molecule antibody targeting intracellular hbx suppresses hepatitis b virus via trim21-dependent pathway. Theranostics, 8:549.

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    Non-proteolytic ubiquitination of HBx controls HBV replication

      Corresponding author: Xiangpeng Sheng, shengxiangpeng@ucas.ac.cn
      Corresponding author: Yumin Xu, xym121@163.com
      Corresponding author: Qing You, youqing@sjtu.edu.cn
      Corresponding author: Ronggui Hu, coryhu@sibcb.ac.cn
    • a. State Key Laboratory for Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150069, China;
    • b. State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China;
    • c. Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China;
    • d. Department of Thoracic Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China;
    • e. Shanghai Key Laboratory of Plant Molecular Sciences, College of Life Sciences, Shanghai Normal University, Shanghai 200234, China;
    • f. Department of Pathogenic Biology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041, China;
    • g. School of Medicine, Guizhou University, Guiyang 550025, China;
    • h. Key Laboratory of Medical Molecular Virology (MOE & MOH), School of Basic Medical Sciences, Fudan University, Shanghai 200032, China;
    • i. Department of Hospital Infection Management, Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China;
    • j. School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China

    Abstract: Highlights
    1. The expression level of TRIM21 in patients is negatively correlated with the replication and integration of HBV.
    2. TRIM21 was found to trigger non-proteolytic ubiquitination of X protein of HBV.
    3. This study proposes that the PRYSPRY and RING domains in TRIM21 dimer can form a docking conformation for HBx binding.
    4. TRIM21-mediated HBx ubiquitination disrupts the DDB1 recruitment to HBx and stabilize Smc6.

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